tbuckley/cabot-search huggingface dataset:
Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding
Authors: Yukiko Kurihara, Toru Ekimoto, Christopher T. Gordon, Yasunobu Uchijima, Ryo Sugiyama, Taro Kitazawa, Akiyasu Iwase, Risa Kotani, Rieko Asai, Véronique Pingault, Mitsunori Ikeguchi, Jeanne Amiel, Hiroki Kurihara
Journal: Journal of Clinical Investigation (2023)

Mutations of G protein-coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here, we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduced the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, which may provide the basis for drug design targeting GPCRs.
An Overview of Ethical Issues Raised by Medicolegal Challenges to Death by Neurologic Criteria in the United Kingdom and a Comparison to Management of These Challenges in the USA
Authors: Ariane Lewis
Journal: The American Journal of Bioethics (2023)

Although medicolegal challenges to the use of neurologic criteria to declare death in the USA have been well-described, the management of court cases in the United Kingdom about objections to the use of neurologic criteria to declare death has not been explored in the bioethics or medical literature. This article (1) reviews conceptual, medical and legal differences between death by neurologic criteria (DNC) in the United Kingdom and the rest of the world to contextualize medicolegal challenges to DNC; (2) summarizes highly publicized legal cases related to DNC in the United Kingdom, including the nuanced 2022 case of Archie Battersbee, who was transiently considered dead by neurologic criteria, but ultimately determined to be in a vegetative state/unresponsive-wakeful state; and (3) provides an overview of ethical issues raised by medicolegal challenges to DNC in the United Kingdom and a comparison to the management of these challenges in the USA.
Rural Residence Is Associated With a Delayed Trend Away From Sulfonylurea Use for Treatment Intensification of Type 2 Diabetes
Authors: Danielle K. Nagy, Lauren C. Bresee, Dean T. Eurich, Scot H. Simpson
Journal: Diabetes Care (2023)

OBJECTIVE To examine the intersection between location of residence along the rural–urban continuum (metropolitan, urban, and rural) and sulfonylurea dispensation records for the management of type 2 diabetes. RESEARCH DESIGN AND METHODS This retrospective cohort study used administrative health records of adult new metformin users between April 2008 and March 2019 in Alberta, Canada. Multivariable logistic regression was performed to examine the association between sulfonylurea-based treatment intensification and location of residence. RESULTS Treatment was intensified in 66,084 (38%) of 171,759 new metformin users after a mean of 1.5 years. At treatment intensification, mean age was 55 years, 62% of users were male, and 27% were rural residents. The most common antihyperglycemic drug, given to 30,297 people (46%) for treatment intensification, was a sulfonylurea. At the beginning of our observation period, the proportion of people dispensed a sulfonylurea at first treatment intensification was highest in rural (57%), compared with urban (54%) and metropolitan (52%) areas (P = 0.009). Although proportions decreased over time across the province, rural residents continued to constitute the highest proportion of sulfonylurea users (45%), compared with urban (35%) and metropolitan (37%) residents (P &amp;lt; 0.001), and the trend away from sulfonylurea use was delayed by ∼4 years for rural residents. Adjusting for potential sources of confounding, rural residence was associated with a significantly higher likelihood of using a sulfonylurea compared with metropolitan residence (adjusted odds ratio 1.34; 95% CI 1.29–1.39). CONCLUSIONS Variation in sulfonylurea dispensation across the rural–urban continuum provides a basis for continued research in the differences in process of care by location.
Research Gets Funding Boost for FY 2023
Journal: Cancer Discovery (2023)

The federal spending bill enacted by the U.S. Congress in December for fiscal year 2023 totals $1.7 trillion, a sum that includes increases ranging from 5.6% to 6.5% for the NCI, NIH, and FDA. The increase for the NCI is positive news overall, but cancer research advocates say greater increases are needed to meet NCI's goal of raising the payline to the 15th percentile by 2025.
The GENESIS-UV study on ultraviolet radiation exposure levels in 250 occupations to foster epidemiological and legislative efforts to combat nonmelanoma skin cancer
Authors: Marc Wittlich, Stephan Westerhausen, Benjamin Strehl, Helmut Versteeg, Wiho  Stöppelmann
Journal: British Journal of Dermatology (2022)

Several hundred million of the 3 billion formally employed people worldwide are at risk from high levels of solar ultraviolet radiation (UVR). Chronic light damage to the skin can lead to nonmelanoma skin cancer (NMSC), especially when irradiation is too high and is acquired for decades. However, data with uniform metrics, high resolution over time and in-depth occupational profiles are not available.To build a worldwide usable matrix of UVR exposure in occupations and to show use cases for the data.One thousand test persons were recruited to wear electronic data logger dosimeters during their working time for 7 months each. The measurements yielded 3.7 billion data points for around 48 000 days with high-quality data capture covering more than 250 occupations and 650 activities. Scientific evaluation of the data included daily and half-hourly means, geographical transfer calculations to the world, threshold exceedance quotas, transcriptome effects, and occupational disease estimates.A compendium for global use is presented. In-depth analyses and the resulting implications for research have been elaborated to directly link exposure data to effects in the human body. Interestingly, the annual irradiances of the different occupations span a wide range of values: from about 650 to 50 standard erythemal doses, with different distributions over the months. Detailed exposure data per occupation were derived, and the risk on an occupational or activity basis assuming different exposure level quotas was quantified. This showed that, for example, in temperate latitudes, all activities with a duration of > 2 h outdoors are associated with increased NMSC risk.We offer our work to enable sound studies on the nature of ultraviolet-induced skin cancer, dose-response relationships, intermittency of skin exposure, and derivation of limit values. Sociological studies on prevention are now possible. Practitioners may use the findings for their daily work with employees.
Cobalt nanoparticles cause allergic contact dermatitis in humans
Authors: Klara Midander, Paulina Werner, Marléne Isaksson, Lukas Wisgrill, Carola Lidén, Nanna Fyhrquist, Anneli Julander
Journal: British Journal of Dermatology (2022)

Cobalt (Co) causes allergic contact dermatitis (ACD) and the emerging use of Co nanoparticles (CoNPs) warrants gaining further insight into its potential to elicit ACD in sensitized individuals.The aims of the study were to clarify to what extent CoNPs may elicit ACD responses in participants with Co contact allergy, and to evaluate whether the nanoparticles cause a distinct immune response compared with cobalt chloride (CoCl2) in the skin reactions.Fourteen individuals with Co contact allergy were exposed to CoNPs, CoCl2, a Co-containing hard-metal disc (positive control), and an empty test chamber (negative control) by patch testing. Allergic responses were evaluated clinically by a dermatologist at Days 2, 4 and 7. At Day 2, patch-test chambers were removed, and remaining test-substance and skin-wipe samples were collected for inductive-coupled plasma mass spectrometry (ICP-MS) analysis. Additionally, skin biopsies were taken from patch-test reactions at Day 4 for quantitative real-time polymerase chain reaction analysis, histopathology and ICP-MS analysis of Co skin penetration.Patch testing with CoNPs elicited allergic reactions in Co-sensitized individuals. At all timepoints, clinical assessment revealed significantly lower frequencies of positive patch-test reactions to CoNPs compared with CoCl2 or to the positive control. CoNPs elicited comparable immune responses to CoCl2. Chemical analysis of Co residues in patch-test filters, and on skin, shows lower doses for CoNPs compared with CoCl2.CoNPs potently elicit immune responses in Co-sensitized individuals. Even though patch testing with CoNPs resulted in a lower skin dose than CoCl2, identical immunological profiles were present. Further research is needed to identify the potential harm of CoNPs to human health.
Estimates of Insulin Out-of-Pocket Cap–Associated Prescription Satisfaction, Adherence, and Affordability Among Medicare Beneficiaries
Authors: Minghui Li, Jing Yuan, Kevin Lu
Journal: JAMA Network Open (2023)

This survey study examines the association of the Inflation Reduction Act of 2022 insulin out-of-pocket cap with prescription satisfaction, adherence, and affordability among Medicare beneficiaries and associated disparities.
Computed tomography scan radiation and brain cancer incidence
Authors: Nicolas R Smoll, Zoe Brady, Katrina J Scurrah, Choonsik Lee, Amy Berrington de González, John D Mathews
Journal: Neuro-Oncology (2023)

Abstract Background Computed tomography (CT) scans make substantial contributions to low-dose ionizing radiation exposures, raising concerns about excess cancers caused by diagnostic radiation. Methods Deidentified medicare records for all Australians aged 0–19 years between 1985–2005 were linked to national death and cancer registrations to 2012. The National Cancer Institute CT program was used to estimate radiation doses to the brain from CT exposures in 1985–2005, Poisson regression was used to model the dependence of brain cancer incidence on brain radiation dose, which lagged by 2 years to minimize reverse causation bias. Results Of 10 524 842 young Australians, 611 544 were CT-exposed before the age of 20 years, with a mean cumulative brain dose of 44 milligrays (mGy) at an average follow-up of 13.5 years after the 2-year lag period. 4472 were diagnosed with brain cancer, of whom only 237 had been CT-exposed. Brain cancer incidence increased with radiation dose to the brain, with an excess relative risk of 0.8 (95% CI 0.57–1.06) per 100 mGy. Approximately 6391 (95% CI 5255, 8155) persons would need to be exposed to cause 1 extra brain cancer. Conclusions For brain tumors that follow CT exposures in childhood by more than 2 years, we estimate that 40% (95% CI 29%–50%) are attributable to CT Radiation and not due to reverse causation. However, because of relatively low rates of CT exposure in Australia, only 3.7% (95% CI 2.3%–5.4%) of all brain cancers are attributable to CT scans. The population-attributable fraction will be greater in countries with higher rates of pediatric scanning.
The 2022 American College of Rheumatology/<scp>EULAR</scp> classification criteria for giant cell arteritis and Takayasu arteritis: comment on the articles by Ponte et al and Grayson et al
Authors: Albrecht Betrains, Lien Moreel, Daniel Blockmans
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Objective and Subjective Sleep Patterns in Adults With Maturity-Onset Diabetes of the Young (MODY)
Authors: Marilyn Arosemena, Maria V. Salguero, Rochelle N. Naylor, Kristen Wroblewski, Esra Tasali, Louis H. Philipson
Journal: Diabetes Care (2023)

OBJECTIVE To examine sleep patterns in adults with maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS Adults with glucokinase (GCK)-MODY and transcription factor (TF)-related MODY (HNF1A, HNF1B, HNF4A) were recruited (n = 24; age 46.0 years, 79% women, BMI 24.7 kg/m2) from The University of Chicago’s Monogenic Diabetes Registry. Sleep patterns were assessed by 2-week wrist actigraphy (total 315 nights), one night of a home sleep apnea test, and validated surveys. RESULTS Overall, compared with established criteria, 29% of participants had sleep latency ≥15 min, 38% had sleep efficiency ≤85%, 46% had wake after sleep onset &amp;gt;40 min, all indicating poor objective sleep quality. Among all participants, 54% had a sleep duration below the recommended minimum of 7 h, 88% reported poor sleep quality, 58% had obstructive sleep apnea, and 71% reported insomnia. Compared with GCK-MODY, participants with TF-related MODY had poorer objective sleep quality and increased night-to-night variability in sleep patterns. CONCLUSIONS Sleep disturbances appear to be common in adults with MODY despite absent traditional risk factors for sleep disorders. Future research investigating the sleep-diabetes relationship is warranted in this population.
The End of Personhood
Authors: Jennifer Blumenthal-Barby
Journal: The American Journal of Bioethics (2023)

The concept of personhood has been central to bioethics debates about abortion, the treatment of patients in a vegetative or minimally conscious states, as well as patients with advanced dementia. More recently, the concept has been employed to think about new questions related to human-brain organoids, artificial intelligence, uploaded minds, human-animal chimeras, and human embryos, to name a few. A common move has been to ask what these entities have in common with persons (in the normative sense), and then draw conclusions about what we do (or do not) owe them. This paper argues that at best the concept of "personhood" is unhelpful to much of bioethics today and at worst it is harmful and pernicious. I suggest that we (bioethicists) stop using the concept of personhood and instead ask normative questions more directly (e.g., how ought we to treat this being and why?) and use other philosophical concepts (e.g., interests, sentience, recognition respect) to help us answer them. It is time for bioethics to end talk about personhood.
Skin programming of inflammatory responses to <i>Staphylococcus aureus</i> is compartmentalized according to epidermal keratinocyte differentiation status
Authors: Kalum Clayton, Daniel J Holbrook, Andres Vallejo, Gemma Porter, Sofia Sirvent, James  Davies, Jenny Pople, Fei Ling Lim, Myron Christodoulides, Marta E Polak, Michael R Ardern-Jones
Journal: British Journal of Dermatology (2022)

Abstract Background Acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored. Objectives Hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models. Methods Explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models. Results Bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins. Conclusions These findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema.
A real-world prospective cohort study of immunogenicity and reactogenicity of ChAdOx1-S[recombinant] among patients with immune-mediated dermatological diseases
Authors: Kumutnart Chanprapaph, Chutima Seree-aphinan, Ploysyne Rattanakaemakorn, Cherrin Pomsoong, Yanisa Ratanapokasatit, Chavachol Setthaudom, Arunee Thitithanyanont, Aphinyaphiwat Suriyo, Thanitta Suangtamai, P Suchonwanit
Journal: British Journal of Dermatology (2022)

Immunogenicity and reactogenicity of COVID-19 vaccines have been established in various groups of immunosuppressed patients; however, studies involving patients with immune-mediated dermatological diseases (IMDDs) are scarce.To investigate the influence of IMDDs on the development of SARS-CoV-2-specific immunity and side-effects following ChAdOx1-S[recombinant] vaccination.This prospective cohort study included 127 patients with IMDDs and 97 participants without immune-mediated diseases who received ChAdOx1-S[recombinant]. SARS-CoV-2-specific immunity and side-effect profiles were assessed at 1 month postvaccination and compared between groups. Immunological (primary) outcomes were the percentages of participants who tested positive for neutralizing antibodies [seroconversion rate (SR)] and those who developed T-cell-mediated immunity demonstrated by an interferon-γ-releasing assay (IGRA) [positive IGRA rate (+IGRA)]. Reactogenicity-related (secondary) outcomes were the unsolicited adverse reactions and worsening of IMDD activity reflected by the uptitration of immunosuppressants during and within 1 month of vaccination.Overall, the SR for the IMDD group was similar to that of participants without immune-mediated conditions (75·6 vs. 84·5, P = 0·101), whereas + IGRA was lower (72·4 vs. 88·7, P = 0·003). Reactogenicity was similar between groups. No severe adverse reaction was reported. By stratifying the participants in the IMDD group according to individual disease, the immunogenicity of the vaccine was lowest in patients with autoimmune bullous diseases (AIBD) (SR 64·5%, +IGRA 62·9%) and highest in patients with psoriasis (SR 87·7%, +IGRA 80·7%). The reverse trend was found for vaccine-related reactions. Immunosuppressants were uptitrated in 15·8% of cases; 75% of these were patients with AIBD.Among participants with IMDDs, ChAdOx1-S[recombinant] showed good immunogenicity among patients with psoriasis, but demonstrated lower levels of immunogenicity for patients with AIBD. Some patients, especially patients with AIBD, should be closely monitored as they may require treatment escalation within 1 month postvaccination.
SETDB1 Modulates Degradation of Phosphorylated RB and Anticancer Efficacy of CDK4/6 Inhibitors
Authors: Zhenlin Huang, Xiang Li, Bo Tang, Hao Li, Jianong Zhang, Rui Sun, Jian Ma, Yunqian Pan, Binyuan Yan, Yingke Zhou, Donglin Ding, Yuqian Yan, Rafael Jimenez, Jacob J. Orme, Xin Jin, Jinjian Yang, Haojie Huang, Zhankui Jia
Journal: Cancer Research (2023)

Abstract Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression. Significance: The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.